This interdisciplinary research program aims to identify the fundamental neurochemical mechanisms of phencyclidine (1-(1-phenylcyclohexyl)-piperidine, PCP) and to elucidate the molecular determinants for the actions of its psychotropic derivatives. We will conduct detailed and quantitative studies of the actions of PCP on well characterized systems from peripheral nervous tissue and will compare these with the behavioral effects of these drugs and their mechanism of action in the central nervous system (CNS). We will obtain quantitative and qualitative details on PCP action on intestinal smooth muscle preparations, on skeletal muscle, and on cardiac muscle preparations. Attention will be given to release and uptake of neurotransmitters affected by PCP derivatives. High affinity binding sites for PCP derivatives will be characterized in different anatomic regions and subcellular fractions of brain as well as in preparations from peripheral organs. The effects of PCP derivatives in brain and on brain tissue will be monitored at the biochemical, histological, neuroanatomical and behavioral levels. PCP-induced effects on spatial alternation performance and on circling behavior will be studied with emphasis on the localization and the kinetics of PCP action. The relation to brain energy metabolism will be established by regional studies on the distribution of 3H-deoxyglucose and 3H-PCP derivatives, with emphasis on structure activity relationships (SAR) and effects of putative antagonists for actions of PCP in the CNS. Levels of ACh and choline in brain regions, as well as turnover of ACh in these regions, will be measured by gas chromatography-mass spectroscopy. The study of molecular determinants for the action of PCP derivatives will integrate all the results from pharmacological studies and will focus on the discriminant structural factors for the variety of actions. The methods of theoretical and physical chemistry, especially quantum chemistry, will be used to analyze the properties of the PCP derivatives, to identify the forces and mechanisms governing the discrete interactions with the receptors, and to elucidate specific molecular (and electronic) mechanisms by which biological responses are generated. The method of quantitative structure activity relationships (OSAR) will be applied to the search for discriminant structural factors for the various actions of PC (Text Truncated - Exceeds Capacity)